Abstract：
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme that mediates many redox reactions in energy metabolism. NAD+ is also a substrate for ADP-ribosylation and deacetylation by poly (ADP-ribose) polymerase and sirtuin, respectively. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) is a NAD+ biosynthesizing enzyme found in the nucleus. Recent research has shown that the maintaining NAD+ levels is critical for sustaining muscle functions both in physiological and pathological conditions. However, the role of Nmnat1 in skeletal muscle remains unexplored. In this study, we generated skeletal muscle-specific Nmnat1 knockout (M-Nmnat1 KO) mice and investigated its role in skeletal muscle. We found that NAD+ levels were significantly lower in the skeletal muscle of M-Nmnat1 KO mice than in control mice. M-Nmnat1 KO mice, in contrast, had similar body weight and normal muscle histology. Furthermore, the distribution of muscle fiber size and gene expressions of muscle fiber type gene expression were comparable in M-Nmnat1 KO and control mice. Finally, we investigated the role of Nmnat1 in muscle regeneration using cardiotoxin-induced muscle injury model, but muscle regeneration appeared almost normal in M-Nmnat1 KO mice. These findings imply that Nmnat1 has a redundancy in the pathophysiology of skeletal muscle.
摘要：
烟酰胺腺嘌呤二核苷酸（NAD）是介导能量代谢中许多氧化还原反应的辅酶。NAD也是通过聚（ADP-核糖）聚合酶和沉默酶进行ADP-核糖基化和脱乙酰的底物，分别。烟酰胺单核苷酸腺苷酰转移酶1(Nmnat1)是在细胞核中发现的NAD+生物合成酶。最近的研究表明，维持NAD水平对于维持生理和病理条件下的肌肉功能至关重要。然而,Nmnat1在骨骼肌中的作用仍有待探索。在这项研究中,我们产生了骨骼肌特异性Nmnat1敲除（M-Nmnat1KO）小鼠，并研究了其在骨骼肌中的作用。我们发现M-Nmnat1KO小鼠骨骼肌中的NAD+水平显著低于对照小鼠。M-Nmnat1KO小鼠，相比之下,有相似的体重和正常的肌肉组织学。此外，在M-Nmnat1KO和对照小鼠中，肌纤维大小的分布和肌纤维类型基因表达的基因表达具有可比性。最后,我们使用心脏毒素诱导的肌肉损伤模型研究了Nmnat1在肌肉再生中的作用，但是M-Nmnat1KO小鼠的肌肉再生几乎正常。这些发现暗示Nmnat1在骨骼肌的病理生理学中具有冗余。
